The Altitude Gene, A Denisovan Gift

January 27, 2015 by

Jan. 23, 2015

By Medical Discovery News

Altitude Gene, A Denisovan Gift

Those traveling to the Himalayas have a tough time adjusting to the harsh altitude. But for those native to Tibet, called the Roof of the World due its location 14,700 feet up, it’s not a problem. That’s because Tibetans have adapted to this harsh environment partly due to a gene they inherited from an extinct species of prehumans called the Denisovans.

Anyone traveling to high altitudes like those in Tibet can get altitude sickness and there is no way to predict who will get it. The severity of it varies according to genetics and the rate of ascent, but it is not influenced by age, gender, physical fitness, or previous altitude experience. Symptoms can include headaches, nausea, dizziness, fatigue, shortness of breath, loss of appetite, and disturbed sleep. Severe symptoms could indicate high altitude cerebral edema, which impairs brain function, progresses rapidly, and can become life-threatening in a matter of hours.

However, Tibetans live at these extreme altitudes without developing these problems. So how did they adapt to such a challenging environment?

Studies have linked the Tibetan’s adaptation to high altitude with several genes, including a unique form of the EXPAS1 gene. This gene responds to low oxygen levels to increase hemoglobin production. However, Tibetans with this gene do not have elevated levels of hemoglobin. This seems counterintuitive, since increasing hemoglobin could increase the amount of oxygen being transported in the blood. This would be advantageous at altitudes where the availability of oxygen is reduced, which then limits the uptake of oxygen in the lungs. On the other hand, increasing red blood cells would also thicken the blood, making it less efficient in distributing oxygen and increasing the risk of stroke. The Tibetan variant of EXPAS1 gene might then be protective, but we don’t know how exactly it works.

We know that the ancestors of Nepal’s Sherpa people carried the Tibetan EXPAS1 gene variant about 30,000 years ago. Today, only Tibetans carry this version of the gene, no other modern humans have it. New data suggests it may have come from an extinct population of prehuman called the Denisovans. So far they have only been found in a cave in the Altai Mountains in southern Siberia in East Central Asia. More proof is needed to eliminate another extinct species, the Neanderthals, who also have a version of EXPAS1 similar to the Tibetan one. This is another example of genes acquired by interbreeding between Homo sapiens and other ancient species. About 5 percent of the genetic information of Australasians is shared with Denisovans, while 2.5 percent of human DNA originates from Neanderthals. Modern humans have bits of DNA from these ancient species that have made important contributions to the success of our genome.

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Artificial Blood

November 12, 2014 by

Nov. 7, 2014

By Medical Discovery News

Red blood cells

In the series “True Blood,” the invention of artificial blood allows vampires to live among humans without inciting fear. In the real world, however, artificial blood would have very different effects, as 85 million units of blood are donated worldwide and there is always a demand for more. An artificial blood substitute free of infectious agents that could be stored at room temperature and used on anyone regardless of blood type would be revolutionary.

That is exactly what a group of scientists at the University of Essex in England are working on, although the search for an artificial blood substitute started 80 years ago. All red blood cells contain a molecule called hemoglobin, which acquires oxygen from the lungs and distributes it to cells throughout the body. Their plan is to make an artificial hemoglobin-based oxygen carrier (HBOC) that could be used in place of blood.

HBOCs are created using hemoglobin molecules derived from a variety of sources, including expired human blood, human placentas, cow blood, and genetically engineered bacteria. The problem is that free hemoglobin, which exists outside the protective environment of red blood cells, breaks down quickly and is quite toxic. Therefore, HBOCs are not approved for use in most of the world due to their ineffectiveness and toxicity.

The active group in hemoglobin that binds to oxygen is called heme, which can actually be quite toxic. Scientists have found a variety of ways to modify hemoglobin to increase its stability but safety issues still remain. If the hemoglobin’s processing system is overwhelmed, a person may develop jaundice, which causes the skin and whites of the eyes to turn yellow. Too much free hemoglobin can also cause serious liver and kidney damage. When free hemoglobins, not whole red blood cells, are infused, the human body’s natural system for dealing and disposing of this molecule is overwhelmed, leading to toxicity. That is why blood substitutes consisting of free hemoglobin have been plagued with problems, such as an increase in deaths and heart attacks.

But scientists involved in this latest effort to produce a blood substitute have been reengineering the hemoglobin molecule. They are introducing specific amino acids, which are the building blocks of proteins, into hemoglobin in an effort to detoxify it. Preliminary results indicate that this approach may work. They have already created some hemoglobin molecules that are much less reactive and are predicted to be less toxic when used in animals or people.

If successful, this HBOC would be a universal product, meaning it could be used on everyone and there would be no need to waste time on testing for blood types. It would also be sterile, free of any of the infectious agents that donated blood must be tested for. Instead of refrigeration, it could have a long shelf life at room temperature, perhaps years, so it could be stockpiled in case of major emergencies. It could even be kept on board ambulances and at remote locations far from hospitals. The search for an effective and nontoxic blood substitute is one the medical field’s Holy Grails, and if proven successful, these scientists may have finally found it.

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Hope for Sickle Cell

September 20, 2014 by

Sept. 19, 2014

By Medical Discovery News

While sickle cell disease has long been studied, a recent discovery revealed that the disease significantly increases the levels of a molecule called sphingosine-1-phosphate (S1P), which is generated by an enzyme called sphingosine kinase 1 (SphK1). Inhibiting the enzyme SphK1 was found to reduce the severity of sickle cell disease in mice, which will hopefully lead to new drugs that target SphK1in order to treat sickle cell disease in humans.

Sickle cell disease is caused by a change in the gene that is responsible for a type of hemoglobin, the protein molecule in red blood cells that carries oxygen. This tiny change results in hemoglobin clumping together, changing the shape of red blood cells.

The name for sickle cell disease actually comes from misshapen red blood cells. Rather than being shaped like a disk, or a donut without a whole, sickle cells are shaped like a crescent, sort of bending over on themselves. The normal shape is critical to red blood cells’ ability to easily travel through blood vessels and deliver oxygen to cells and tissues. Sickle cells become inflexible and stick to each other, blocking the flow of blood through blood vessels.

Symptoms of the disease begin to appear at about four months of age. Normally, red blood cells live for about 120 days. Sickle cells only survive 10-20 days. Although the bone marrow tries to compensate for the rapid loss of red blood cells, it cannot keep up. The disease causes pain, anemia, organ damage, and possibly infections.

Although the symptoms and their severity vary, most people with sickle cell disease will have periodic crises lasting hours or days. Symptoms include fatigue, paleness, shortness of breath, increased heart rate, jaundice, and pain. Long-term damage can occur in the spleen, eyes, and other organs, and sickle cell disease increases the risk of stroke. People who only inherit one copy of the sickle cell hemoglobin gene have a milder case of the disease than those who inherit two copies, one from each parent.

Current treatments only reduce the number and the severity of crises using hydroxyrurea, blood transfusions, pain medications, and antibiotics. As the disease advances, dialysis, kidney transplants, eye surgeries, gall bladder removal, and other treatments may be necessary. The only cure for the disease is a bone marrow transplant, which is not an option for everyone.

So it’s pretty exciting that when scientists found that levels of S1P were elevated in mice with sickle cell disease, they inhibited the enzyme SphK1 to reduce the levels of S1P. As a result, red blood cells lived longer and had less sickling. The mice also had less inflammation and tissue damage, which would reduce damage to red blood cells and prevent symptoms of the disease. When they engineered sickle cell disease mice without the gene for the enzyme SphK1 that makes S1P, again the mice had less sickling and symptoms.

How does S1P influence sickling? Apparently, it binds directly to hemoglobin and reduces its ability to collect and carry oxygen, which causes the characteristic folding of cells. S1P has other roles in the body, so it is unknown whether inhibitors to SphK1 can safely and effectively be used in humans to treat sickle cell disease.

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Reducing Sickle Cell Disease

March 11, 2012 by

By Medical Discovery News

Feb. 25, 2012

Reversing Sickle Cell Disease

Human red blood cells do an amazing job – transporting needed oxygen to every part of the body. However, in some people, red blood cells are not smooth, round discs that move easily through the blood vessels. Instead, they are crescent or sickle-shaped, which not only block tiny blood vessels called capillaries, but break apart and die prematurely. For a person living with these deformed red blood cells, this results in pain, anemia, stroke, organ dysfunction and damage, and eventually death.

What’s interesting about this disease, called sickle cell, is it doesn’t afflict a developing fetus. The disease develops three to six months after delivery. Now researchers at Harvard Medical School in Boston and the University of Texas at Austin have found a way to get diseased adult mice to switch to their ability to make the healthy red blood cells they made as fetuses. This switch is a gene called BCL11A, and it affects the body’s production of fetal hemoglobin.

Healthy red blood cells are filled with hemoglobin, an iron-rich protein that carries oxygen from the lungs to the rest of the body. With sickle cell, an inherited disease, infants get two copies of a mutated gene that makes hemoglobin with a reduced ability to carry oxygen, and that form into long rods, stretching the cell into a crescent shape.

However, the cells don’t begin to sickle until an infant is a few months old. Researchers discovered that BCL11A switches the body from making fetal hemoglobin, which does not sickle, to adult hemoglobin, which does. Dr. Stuart Orkin, who led the team of researchers who identified BCL11A, found when they blocked the gene in diseased mice, the rodents’ bodies began producing fetal hemoglobin again. These cells did not sickle, and soon after, disease symptoms improved without compromising red blood cell production.

Remarkably, 85 percent of all the red blood cells had some fetal hemoglobin. Inside these cells, fetal hemoglobin represented 30 percent of the total hemoglobin. This is enough fetal hemoglobin to keep cells from sickling.

There is a drug called hydroxyurea, which helps the body produce fetal hemoglobin, but patients can suffer bad side effects. The only existing cure for sickle cell disease is a bone marrow transplant, but finding a match is challenging and the procedure is risky.

Considering the few treatments available to people with sickle cell, this latest discovery is significant. However, the method won’t be tried on humans for years because it’s unlikely the only function for BCL11A is as a switch for the production of fetal hemoglobin. Researchers must determine not only its other functions, but other consequences of turning it off. If this therapy works, it has the potential to make a significant impact since three to five million people worldwide suffer from sickle cell disease.

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